MPAH_PENRF
ID MPAH_PENRF Reviewed; 433 AA.
AC W6QL41;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 29.
DE RecName: Full=Type I acyl-CoA thioesterase mpaH {ECO:0000303|PubMed:26751579};
DE EC=3.1.1.- {ECO:0000305|PubMed:26751579};
DE AltName: Full=Mycophenolic acid biosynthesis cluster protein H {ECO:0000303|PubMed:26751579};
GN Name=mpaH {ECO:0000303|PubMed:26751579}; ORFNames=PROQFM164_S05g000554;
OS Penicillium roqueforti (strain FM164).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=1365484;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=FM164;
RX PubMed=24407037; DOI=10.1038/ncomms3876;
RA Cheeseman K., Ropars J., Renault P., Dupont J., Gouzy J., Branca A.,
RA Abraham A.L., Ceppi M., Conseiller E., Debuchy R., Malagnac F., Goarin A.,
RA Silar P., Lacoste S., Sallet E., Bensimon A., Giraud T., Brygoo Y.;
RT "Multiple recent horizontal transfers of a large genomic region in cheese
RT making fungi.";
RL Nat. Commun. 5:2876-2876(2014).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=26751579; DOI=10.1371/journal.pone.0147047;
RA Del-Cid A., Gil-Duran C., Vaca I., Rojas-Aedo J.F., Garcia-Rico R.O.,
RA Levican G., Chavez R.;
RT "Identification and functional analysis of the mycophenolic acid gene
RT cluster of Penicillium roqueforti.";
RL PLoS ONE 11:E0147047-E0147047(2016).
CC -!- FUNCTION: Type I acyl-CoA thioesterase; part of the gene cluster that
CC mediates the biosynthesis of mycophenolic acid (MPA), the first
CC isolated antibiotic natural product in the world obtained from a
CC culture of Penicillium brevicompactum in 1893 (PubMed:26751579). MpaH
CC acts as a peroxisomal acyl-CoA hydrolase that converts MPA-CoA into the
CC final product MPA (By similarity). The first step of the pathway is the
CC synthesis of 5-methylorsellinic acid (5MOA) by the cytosolic polyketide
CC synthase mpaC. 5MOA is then converted to the phthalide compound 5,7-
CC dihydroxy-4,6-dimethylphthalide (DHMP) by the endoplasmic reticulum-
CC bound cytochrome P450 monooxygenase mpaDE. MpaDE first catalyzes
CC hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-
CC methylbenzoic acid (DHMB). MpaDE then acts as a lactone synthase that
CC catalyzes the ring closure to convert DHMB into DHMP. The next step is
CC the prenylation of DHMP by the Golgi apparatus-associated
CC prenyltransferase mpaA to yield farnesyl-DHMP (FDHMP). The ER-bound
CC oxygenase mpaB then mediates the oxidative cleavage the C19-C20 double
CC bond in FDHMP to yield FDHMP-3C via a mycophenolic aldehyde
CC intermediate. The O-methyltransferase mpaG catalyzes the methylation of
CC FDHMP-3C to yield MFDHMP-3C. After the cytosolic methylation of FDHMP-
CC 3C, MFDHMP-3C enters into peroxisomes probably via free diffusion due
CC to its low molecular weight. Upon a peroxisomal CoA ligation reaction,
CC catalyzed by a beta-oxidation component enzyme acyl-CoA ligase ACL891,
CC MFDHMP-3C-CoA would then be restricted to peroxisomes for the following
CC beta-oxidation pathway steps. The peroxisomal beta-oxidation machinery
CC than converts MFDHMP-3C-CoA into MPA_CoA, via a beta-oxidation chain-
CC shortening process. Finally mpaH acts as a peroxisomal acyl-CoA
CC hydrolase with high substrate specificity toward MPA-CoA to release the
CC final product MPA (PubMed:26751579) (Probable).
CC {ECO:0000250|UniProtKB:A0A0B5LB55, ECO:0000269|PubMed:26751579,
CC ECO:0000305|PubMed:26751579}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + mycophenolyl-CoA = CoA + H(+) + mycophenolate;
CC Xref=Rhea:RHEA:66704, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:62932, ChEBI:CHEBI:167447;
CC Evidence={ECO:0000250|UniProtKB:A0A0B5LB55};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66705;
CC Evidence={ECO:0000250|UniProtKB:A0A0B5LB55};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:26751579}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:A0A0B5LB55}.
CC -!- SUBCELLULAR LOCATION: Peroxisome matrix
CC {ECO:0000250|UniProtKB:A0A0B5LB55}. Note=The mpaH' location in
CC peroxisomes is required for the unique cooperation between biosynthetic
CC and beta-oxidation catabolism machineries to produce final MPA.
CC {ECO:0000250|UniProtKB:A0A0B5LB55}.
CC -!- DISRUPTION PHENOTYPE: Results in dramatic reduction in MPA production.
CC {ECO:0000269|PubMed:26751579}.
CC -!- SIMILARITY: Belongs to the AB hydrolase superfamily. MpaH hydrolase
CC family. {ECO:0000305}.
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DR EMBL; HG792019; CDM36721.1; -; Genomic_DNA.
DR AlphaFoldDB; W6QL41; -.
DR SMR; W6QL41; -.
DR ESTHER; penrf-mpah; MpaH.
DR EnsemblFungi; CDM36721; CDM36721; PROQFM164_S05g000554.
DR OrthoDB; 1261667at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000030686; Unassembled WGS sequence.
DR GO; GO:0005782; C:peroxisomal matrix; ISS:GO_Central.
DR GO; GO:0016787; F:hydrolase activity; ISS:GO_Central.
DR GO; GO:0140722; P:mycophenolic acid biosynthetic process; ISS:GO_Central.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR000073; AB_hydrolase_1.
DR Pfam; PF12697; Abhydrolase_6; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 3: Inferred from homology;
KW Hydrolase; Peroxisome.
FT CHAIN 1..433
FT /note="Type I acyl-CoA thioesterase mpaH"
FT /id="PRO_0000449214"
FT REGION 58..246
FT /note="Abhydrolase domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 139
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT ACT_SITE 163
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT ACT_SITE 365
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT BINDING 60
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
FT BINDING 140
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A0A0B5LB55"
SQ SEQUENCE 433 AA; 48633 MW; DC67088F2174D14E CRC64;
MSSEKFTVTE HLVPGSYIRE YPGSTVTQED VLKIHVKQYT PKHEGPVPAD AITFIAAHGV
GLPKELYEPL WDELLERTNG FHIHGIWVAD VASMNQSGIQ NEDKLSMDCS WMDHPRDLFL
MINHFREQMP RPLVGVGHSF GGNIITNLAY LHPRLFTTLL LIDPLIQLSP PSMGFGTDPP
GPINYTLWRN DVWPSREAAI RANRGLIHGW DPRCVDRMAK YFFRDLPTPL YPDVEAVKAR
FDAAADTTAT PVTLATPKYH ELIAQIRQNF NARDPTTGRI EIPRATHADM DPLVASIPLY
RPEPRSTFRR LGTLRPSCLW IVGGATFLNV DEIHEGVKIC GSGIGGSGGV SEGRVKEVIL
PGLGHLMPFQ EIGTVVGPCV AWLQQEMDRF RQMEREWGEE RKGKSHLVLE KNWYKVLKPM
PSGRGKGGRK EKL
